Development and function in mucociliary epithelia

摘要： 粘膜纤毛上皮在正常和病理性气道生物学中起关键作用，因为它提供了呼吸系统的功能。 是对抗吸入性毒剂的第一道防线气道多纤毛细胞纤毛搏动缺陷 有助于遗传性和获得性气道疾病的进展。 在这里，我们将研究控制MCCs的发育和功能的分子机制。马达 驱动纤毛跳动的蛋白质在细胞质中组装，并且在此之前的版本中， 我们发现了一种新的细胞器，其中这些马达集中了各种因素， 他们的集会。本项目的第一个目的是探索这些蛋白质之间相互作用的层次结构， 新的细胞器;第二个将探讨电机被运送到纤毛的机制，以及 第三个将使用大规模销售的蛋白质组学方法来识别对运动重要的新蛋白质-蛋白质相互作用。 组装和功能。通过快速测定几种新的蛋白质的功能， 在MCC开发过程中，本提案中的目标将为我们的理解提供关键的新深度 这些重要的细胞。此外，通过将MCC中的这些不同过程联系起来，这里的实验将 也为我们的理解增加了重要的新广度。 影响：这里提出的实验将导致对细胞生物学和遗传学的更详细的了解。 MCC和纤毛跳动研究结果将有助于开发再生疗法， 修复或恢复受损的组织并改善气道疾病患者的粘液清除。

Abstract: The mucociliary epithelium plays a key role in both normal and pathological airway biology, as it provides the first line of defense against inhaled agents. Defects in ciliary beating in multiciliated cells (MCCs) in the airway contribute to the progression of both genetic and acquired airway diseases. Here, we will study the molecular mechanisms controlling development and function of MCCs. The motor proteins that drive ciliary beating are assembled in the cytoplasm, and under the previous version of this award, we discovered a novel organelle in which these motors are concentrated with various factors that direct their assembly. The first Aim of this project will explore the hierarchy of interaction among proteins in these novel organelles; the second will explore the mechanisms by which motors are transported into cilia, and the third will use large-sale proteomic approaches to identify novel protein-protein interactions important for motor assembly and function. By rapidly determining the functions of several new protein involved in distinct processes in MCC development, the Aims in this proposal will provide critical new depth to our understanding of these essential cell. Moreover, by linking these the disparate processes in MCCs, the experiments here will add crucial new breadth to our understanding as well. Impact: Experiments proposed here will lead to a more detailed understanding of the cell biology and genetics of MCCs and ciliary beating. The results will aid in the development of regenerative therapies aimed at repairing or restoring damaged tissue and improving mucus clearance in patients with airway disease.